Unexplained sudden death is common among patients (pts) with sickle cell diseases (SCD). QTc prolongation is a risk factor for fatal arrhythmias among adults. Cardiovascular autonomic dysfunction has been proposed as a contributing cause for sudden death in SCD but QTc prolongation has only been described in isolated pediatric case reports. Purpose: To investigate the incidence of QTc prolongation among adults with SCD and the relationship between prolonged QTc interval and sudden death. Methods: We reviewed records of 180 consecutive adults with SCD from October 1996 to January of 2007. EKGs and echocardiograms (Echo) were independently reviewed by a cardiologist who was blinded to the patients' clinical and laboratory data. Bazett's formula was used to calculate QTc interval. In pts with more than one EKG, the longest QTc data was used for analysis. Results: SCD were divided into 3 groups: homozygous SS = 113 (67%), SC = 34 (20%), Sβthal = 21 (13%). Mean age was 35 years (range 25–45), 66 (58%) were females, 108 (96%) were African American and 4% were Mexican. Other medical problems were prior CVA in 17, congestive heart failure in 11, hypertension in 9, renal insufficiency in 13, and diabetes in 7. Medications included hydroxyurea in 41, methadone in 38, other narcotics in 41, ACE inhibitors in 16 and beta blockers in 16. Twenty five pts were receiving chronic exchange transfusions. EKGs were available in 113 (67%) and Echo in 95 (53%). Serum chemistries and ferritin were available in 110 pts within 24 hours of the EKG and in 3 pts within 48 hours. QTc intervals were prolonged (>440 msec) in 74 pts (66%). Sixty six pts (47%) pts had more than one EKG with prolonged QTc. QTc intervals increased progressively over 4 years from a mean 434 msec (415–452) to mean 462 msec (446–487), (p=<0.001). In univariate analysis, there was a positive correlation between QTc prolongation and the following: prolongation of QRS, increased left ventricular end diastolic dimension, decreased ejection fraction, elevated pulmonary artery systolic pressure, elevated ferritin, decreased creatinine clearance and methadone use. In multivariate analysis elevated ferritin levels had the most significant association (p= 0.008). Eighteen pts died over the 5 years (15.9%). Causes of death were pulseless electrical activity in 3, sepsis in 3 and unknown in 12. Identified risk factors for death were QTc prolongation (p=0.017), prolonged QRS (p=0.011), increased septal thickness (p=0.038), elevated pulmonary artery pressure (p=0.001), decreased left ventricular ejection fraction (p=0.001) and renal failure (p<0.001). There was a significant difference in QTc interval between living and deceased pts with QTc of 452.5 msec (430–477) vs. 469(433.5–538.25) msec (p=0.017). Conclusions: Prolongation of QTc is common among adults with SCD and is associated with other cardiac abnormalities that are directly related to sudden death. Elevated ferritin (presumably from iron overload) appears to be the most significant factor associated with prolongation of QTc. These findings suggest that serial monitoring of EKG, electrolytes and ferritin should be part of the standard care in SCD pts. Exchange transfusions are preferable in stable conditions to minimize iron overload. Careful consideration should be given to the choice of analgesics and the use of drugs such as macrolide antibiotics and tricyclic antidepressants that could further prolonged the QTc and cause life threatening arrhythmias.